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J. Biol. Chem., Vol. 277, Issue 36, 33235-33241, September 6, 2002
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From the The purpose of this study is to examine the
regulation of blood pressure and fluid and electrolyte homeostasis in
mice overexpressing angiotensin II (Ang-II) in the brain and to
determine whether there are significant physiologic differences in
Ang-II production in neurons or glia. Therefore, we generated and
characterized transgenic mice overexpressing human renin (hREN) under
the control of the glial fibrillary acidic protein (GFAP) promoter
(GFAP-hREN) and synapsin-I promoter (SYN-hREN) and bred them with mice
expressing human angiotensinogen (hAGT) under the control of the same
promoters (GFAP-hAGT and SYN-hAGT). Both GFAP-hREN and SYN-hREN mice
exhibited the highest hREN mRNA expression in the brain and had
undetectable levels of hREN protein in the systemic circulation. In the
brain of GFAP-hREN and SYN-hREN mice, hREN protein was observed almost exclusively in astrocytes and neurons, respectively. Transgenic mice
overexpressing both hREN and hAGT transgenes in either glia or neurons
were moderately hypertensive. In the glia-targeted mice, blood pressure
could be corrected by intracerebroventricular injection of the Ang-II
type 1 receptor antagonist losartan, and intravenous injection of
a ganglion blocking agent, but not an arginine vasopressin
V1 receptor antagonist, lowered blood pressure. These data suggest that
stimulation of Ang-II type 1 receptors in the brain by Ang-II derived
from local synthesis of renin and angiotensinogen can cause an
elevation in blood pressure via a mechanism involving enhanced
sympathetic outflow. Glia- and neuron-targeted mice also exhibited an
increase in drinking volume and salt preference, suggesting that
chronic overexpression of renin and angiotensinogen locally in the
brain can result in hypertension and alterations in fluid homeostasis.
Glia- and Neuron-specific Expression of the
Renin-Angiotensin System in Brain Alters Blood Pressure, Water Intake,
and Salt Preference*
§,
Departments of Internal Medicine and
Physiology & Biophysics and the ¶ Department of Anatomy and Cell
Biology, Roy J. and Lucille A. Carver College of Medicine, University
of Iowa, Iowa City, Iowa 52242
*
The work described herein was funded by National Institutes
of Health Grants HL58048, HL61446, and HL55006.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence and reprint requests should be
addressed: Depts. of Internal Medicine and Physiology & Biophysics, 3181B Medical Education and Biomedical Research Facility, University of
Iowa College of Medicine, Iowa City, IA 52242. Tel.: 319-335-7604; Fax:
319-353-5350; E-mail: curt-sigmund@uiowa.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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